This invention relates to compounds and methods for treating prostaglandin mediated diseases, certain pharmaceutical compositions thereof, and the like. More particularly, the compounds of the invention are structurally different from nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from The British Journal of Pharmacology (1994, 112, 735-740) suggests that Prostaglandin E.sub.2 (PGE.sub.2) exerts allodynia through the EP.sub.1 receptor subtype and hyperalgesia through EP.sub.2 and EP.sub.3 receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, will have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug and, in addition, will inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects. In The American Physiological Society (1994, 267, R289-R-294), studies suggest that PGE.sub.2 -induced hyperthermia in the rat is mediated predominantly through the EP.sub.1 receptor. World patent applications WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1 (Jan. 8, 1997) disclose compounds represented by Formula I as being useful in the treatment of prostaglandin mediated diseases. ##STR2##
wherein:
A is phenyl, naphthyl, 5- or 6-membered heteroaryl; PA1 B is phenyl, 5- or 6-membered heteroaryl or a keto-dihydro ring; PA1 D is phenyl, 5- or 6-membered heteroaryl; PA1 R.sup.1 is COOH, (CH.sub.2).sub.n COOH, tetrazolyl(alkyl); PA1 R.sup.3 is H, alkyl; PA1 Z is an alkylene bridge; PA1 Ia is one of the compounds specifically claimed. PA1 A and B are independently unsubstituted, monosubstituted or disubstituted ortho-benzenediyl or ortho-heteroarylenediyl wherein the substituents are selected from the group consisting of: PA1 X is CH.sub.2 CH.sub.2, CH.dbd.CH, CH.sub.2 Y, YCH.sub.2, CH.sub.2 CH.sub.2 CH.sub.2, ortho-benzenediyl or ortho-heteroarylenediyl; PA1 Y is O, S, CF.sub.2, or C.dbd.O; PA1 D is unsubstituted, monosubstituted, or disubstituted benzendiyl wherein the substituents are selected from: PA1 R is: PA1 n=0, 1, 2 or 3; PA1 R.sup.1 and R.sup.2 are independently hydrogen, C.sub.1-3 alkyl, benzyl, C.sub.1-3 fluoroalkyl, C.sub.1-3 alkoxy,or fluorine; PA1 R.sup.3 is H or C.sub.1-6 alkyl. PA1 A and B are independently unsubstituted, monosubstituted or disubstituted ortho-benzenediyl wherein the substituents are selected from the group consisting of: PA1 X is CH.sub.2 CH.sub.2, CH.dbd.CH, CH.sub.2 Y, YCH.sub.2, CHCH.sub.2 CH, ortho-benzenediyl or ortho-heteroarylenediyl; PA1 Y is O or S; PA1 D is unsubstituted or monosubstituted benzendiyl wherein the substituents are selected from: PA1 R is: PA1 n=0, 1, 2 or 3; PA1 R.sup.1 and R.sup.2 are independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl, or C.sub.1-3 alkoxy; PA1 R.sup.3 is H or C.sub.1-6 alkyl. PA1 A and B are independently unsubstituted, monosubstituted or disubstituted ortho-benzenediyl wherein the substituents are halogen; PA1 X is CH.sub.2 CH.sub.2, CH.dbd.CH, or OCH.sub.2 ; PA1 D is benzendiyl; PA1 R is: PA1 n=0,1, 2 or 3; PA1 R.sup.1 and R.sup.2 are independently hydrogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl, or C.sub.1-3 alkoxy; PA1 R.sup.3 is H or C.sub.1-3 alkyl. PA1 (i) all the end products of the formula II were analyzed by NMR, TLC and mass spectrometry; PA1 (ii) intermediates were analyzed by NMR and TLC; PA1 (iii) most compounds were purified by flash chromatography on silica gel, recrystallization and/or swish (suspension in a solvent followed by filtration of the solid) with a solvent such as ether:hexane 1:1; PA1 (iv) the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; PA1 (v) temperatures are in degrees Celsius.